P651: REAL-WORLD EFFECTIVENESS OF VENETOCLAX-BASED REGIMENS IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IN ISRAEL: UPDATE FROM THE MULTICENTER PROSPECTIVE REVEAL STUDY
Authors: Yair Herishanu, Neta Goldschmidt, Gilad Itchaki, Yotam Bronstein, Itai Levi, Ariel Aviv, Riva Fineman, Najib Dally, Tamar Tadmor, Aaron Ronson, Uri Abadi, Levi Shvidel, Galia Stemer, Sigi Kay, Chen Glait Santar, Moran Barak, Noa Rivlin, Natalie Kaminsky, Raanan Cohen, Keren Ofek, Jenia Berelovich, Moshe Grunspan, Ohad Benjamini
Journal: HemaSphere (2023)

Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody has demonstrated improved outcomes and manageable safety compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL) patients (pts). Aims: To study the effectiveness and safety of venetoclax-based treatment in a real-life setting. Methods: A prospective observational multicenter study of pts with CLL/SLL was conducted in Israel. Treatment-naïve (TN) and relapsed or refractory (R/R) pts were enrolled at the time of venetoclax-based therapy initiation. Demographic, baseline characteristics, clinical outcomes and safety data were documented. The primary endpoint was 12-month clinical overall response rate (ORR) per physician assessment. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and 12-month peripheral blood undetectable measurable residual disease (uMRD) rate as assessed centrally by flow-cytometry (<10-4). Herein, we report the updated effectiveness and safety results. Results: Between February 10, 2019 and September 18, 2022 (data cut-off), 286 CLL pts were enrolled; 142 were TN and 144 R/R with a median age of 68 (range 34-85) and 70 (range 25-91), respectively. Among R/R pts, the median number of prior lines of therapy was 1 (range 1-8) and 74 of them (51.4%) were previously exposed to B-cell receptor inhibitors (BCRi). The majority of TN pts (n=131, 93%) were treated with venetoclax plus obinutuzumab, and in R/R pts; 103 (72%), 16 (11%) and 24 (17%) received venetoclax with rituximab, with obinutuzumab (although off-label) and as monotherapy, respectively. Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 86% (n=122) of TN and 83% (n=120) of R/R patients. The 12-month clinical ORR for TN pts was 89% (70% complete response (CR) and 19% partial response (PR)) and for R/R pts 90% (64% CR and 26% PR). The 12-month uMRD rate was 89% (49/55 out of evaluated pts) in TN and 73% (56/77 out of evaluated pts) in R/R. At a median follow-up of 13.1 months range 0.03-34.8) for TN and 22.0 months (range 0.02-41.2) for R/R, the estimated 12 and 24-months PFS were 92% and 80% for TN and 83% and 66% for R/R respectively. Within the R/R cohort the estimated 12 and 24-months PFS were 89% and 70% for pts treated with venetoclax plus an anti-CD20 and 52% and 41% for pts treated with venetoclax monotherapy. The estimated 12 and 24-months PFS, for del17p/TP53mut, were 90% and 75% in TN and 73% and 42% in R/R, respectively and 92% and 84% in R/R BCRi naïve versus 74% and 49% in BCRi-exposed pts, respectively (Table 1). At data cut-off, 40 deaths occurred: 10 (7.1%) in TN and 30 (20.8%) in R/R. The estimated 12 and 24-months OS for TN pts were 94% and 85%, respectively, and for RR pts 89% and 78% respectively. Grade ≥3 adverse events (AEs) were reported in 61 (43%) of TN and 81 (56%) of R/R patients. In line with previous studies, the most frequent grade ≥3 AEs documented were neutropenia (TN 23%, R/R 38%), Covid-19 infection (TN 6%, R/R: 9%) and anemia (TN: 2%, R/R 8%). TLS occurred in one (0.7%) TN patient and in 8 (5.6%) R/R pts, of which 2 were reported as clinical TLS. Summary/Conclusion: In routine clinical practice treatment with venetoclax-based regimens for TN and R/R CLL/SLL, demonstrate good clinical efficiency with deep responses and a favorable safety profile. In R/R pts, previous exposure to BCRis, del17p/TP53mut, and venetoclax monotherapy are associated with inferior clinical outcomes.Keywords: Chronic lymphocytic leukemia, Minimal residual disease (MRD), Real world data, MRD